This invention relates to compositions and methods for delivery of drugs. More particularly, the invention relates to pressure sensitive adhesive matrix patches and methods of use thereof for transdermal delivery of hydrophilic salts of pharmaceutical agents.
Transdermal delivery of various drugs is well known in the art of drug delivery. Pressure sensitive adhesive matrix patches for transdermal delivery of drugs are also known in the art. These matrix patches typically include an inert, impervious backing layer, a pressure sensitive adhesive layer containing the drug and optional selected excipients, and a release liner that is peeled off and discarded before applying the patch to the skin. Suitable pressure sensitive adhesives include polysiloxanes, polyacrylates, polyisobutylene, and the like. These pressure sensitive adhesive polymers are very hydrophobic and are typically purchased as solutions of polymer dissolved in organic solvents. The drug and selected excipients, if any, are directly incorporated into the organic-solvent-based pressure sensitive adhesive solution, mixed, cast as a thin film, and dried to evaporate the solvents, leaving a dried adhesive matrix film containing the drug and excipients. It is well known in the art that the drug has to be hydrophobic to be incorporated into the organic-solvent-based, hydrophobic adhesive. Hydrophilic salt forms of a drug are generally not compatible with such organic-solvent-based pressure sensitive adhesives and have to be converted to the more hydrophobic free acid or free base form for incorporation into the organic-solvent-based, hydrophobic adhesive.
Keshary et al., U.S. Pat. No. 5,002,773, describe transdermal delivery of a calcium antagonist compound, "TA-3090," to patients in need of a calcium channel blocking effect. Keshary et al. state that the free base form of TA-3090 can generally be incorporated in polymeric matrix materials in a higher percent by weight than the maleate salt form of TA-3090 and that the free base form is preferred for transdermal delivery. Chandrasekaran et al., U.S. Pat. No. 4,201,211, disclose a gelled mineral oil-polyisobutylene-clonidine free base skin patch for antihypertensive effect, whereas the hydrochloride salt is used in the manufacture of oral clonidine tablets. Urquhart et al., U.S. Pat. No. 4,262,003, describe a gelled mineral oil-polyisobutylene-scopolamine free base transdermal patch for the administration of scopolamine base to inhibit nausea and emesis. These examples illustrate the conversion of a hydrophilic salt form of a drug into the more hydrophobic free base form to render it more compatible for incorporation into a hydrophobic pressure sensitive adhesive matrix patch.
Water-based pressure sensitive adhesives are also commercially available. These water-based adhesives are formulated as emulsions wherein the hydrophobic pressure sensitive adhesive polymer is dispersed in water with the help of surfactants. Such water-based adhesives provide inherent advantages of safety and reduced environmental problems over solvent-based pressure sensitive adhesives, because the carrier is water and not an organic solvent. These water-based adhesives are widely used in the manufacture of medical tapes and bandages, and provide excellent skin adhesion.
Coughlan et al., U.S. Pat. No. 4,564,010, disclose a pressure sensitive adhesive film for medical use comprising a base layer laminated to a water-based pressure sensitive adhesive coating formed of a mixture of a polyacrylic latex, an ester resin, and a thickening agent. Coughlan et al. teach that such films can be used in transdermal delivery systems, however, they fail to describe the types of drugs that may be suitable for transdermal delivery with such a system. Yeh et al., U.S. Pat. No. 5,230,896, describe a transdermal delivery system for administration of nicotine comprising nicotine base, an acrylic polymer adhesive, a stabilizer, and a polyester film backing. It is stated that a nicotine salt is also contemplated in the practice of the invention. Such a nicotine salt is used to reduce volatility of the drug and is formed in situ by addition of acid. When an acid is used to produce the nicotine salt, an emulsion thickener is also required to increase the viscosity of the formulation. Nicotine is a unique compound in that both the free base and its salt forms are very water soluble. Sablotsky et al., U.S. Pat. No. 5,186,938, describe the use of a water-based emulsion adhesive patch for the transdermal administration of nitroglycerin.
Hydrophilic salt forms of hydrophobic drugs are generally readily soluble in water-based pressure sensitive adhesives because the solvent is water, not an organic solvent. What has hitherto gone unrecognized, and is the subject matter of the present invention, is that the hydrophilic salt form of a hydrophobic drug can not only be readily incorporated into the water-based hydrophobic pressure sensitive adhesive, but that the drug is then readily permeable across skin from the dried adhesive film. In fact, the skin flux of the hydrophilic salt form of a drug from a water-based pressure sensitive adhesive matrix is comparable to that of the hydrophobic free base or free acid form from an organic solvent-based pressure sensitive adhesive matrix patch. This finding is novel and contrary to conventional wisdom, which holds that hydrophilic compounds are much less permeable across skin than more hydrophobic substances. R. J. Scheuplein et al., Permeability of the Skin, 51 Physiological Reviews 702-47 (1972); G. L. Flynn, Mechanisms of Percutaneous Absorption from Physicochemical Evidence, in Percutaneous Absorption 27-51 (R. L. Bronaugh & H. I. Maibach eds., Marcel Decker, Inc. 1989). Gale et al., U.S. Pat. Nos. 4,645,502 and 4,904,475, disclose a reservoir patch device for transdermal delivery of highly ionized, fat-insoluble drugs. This invention is premised on the observation that unionized forms of most drugs are more permeable through skin than their ionized forms, i.e. the salt of a particular drug generally cannot be delivered through skin without significant permeation enhancement. For example, Keshary et al., U.S. Pat. No. 5,002,773, show that the free base form of TA-3090 is 7-10 fold more permeable than the maleate salt of TA-3090 from organic solvent based pressure sensitive adhesive matrix systems. In view of the foregoing, it will be appreciated that compositions and methods for efficient transdermal delivery of hydrophilic salt forms of drugs with hydrophobic pressure sensitive matrix patches would be a significant advancement in the art.